Significance Despite the fact that non-oncogenic pulmonary diseases are the third leading cause of death in the U.S. and a major factor in morbidity and disability, and that pulmonary cancer is the leading cause of cancer-related deaths, understanding of the cellular and metabolic mechanisms by which major etiologic factors, such as tobacco smoke and industrial chemicals, has relied primarily on studies in laboratory rodents whose lungs are different than primates. Objectives Three hypotheses are being tested 1) the rhesus macaque, which is anatomically and cellularly similar to humans, is an appropriate surrogate for humans for evaluating chemical-induced lung toxicity; 2) the cellular distribution of monooxygenases in humans and non-human primate lungs is highly focal making those cells particularly susceptible to cytotoxicants; 3) the catalytic activities of pulmonary P450's in monkeys are similar to those in humans. Results The toxicity of three rodent lung toxicants, naphthalene, nitronaphthalene and ipomeanol, is being evaluated in vitro in lungs of rhesus monkeys and compared to humans and rodents using a special isolated lung technique developed specifically for defining cytotoxicity in small groups of epithelial cells from specific microenvironments within the respiratory system. These data are being compared with responses of rhesus monkeys exposed in vivo. The cellular distribution of P450's responsible for the bioactivation of lung toxicants in rodents is being defined in rhesus monkey and human lungs. Future Directions We are continuing these studies to include sufficient number of animals to demonstrate differences. KEYWORDS cytochrome P450's, lung toxicity, metabolic activation FUNDING NIH Grants ES 08408 and ES00628